Leptin receptor

The leptin receptor belongs to the gp130 family of cytokine receptors (Tartaglia LA et al. 1995). Via its cytosolic domain, the leptin receptor is associated with tyrosine kinases as it does not have its own tyrosine kinase activity.

Alternative splicing produces the 6 leptin receptor isoforms: ObRa, ObRb, ObRc, ObRd, ObRe and ObRf (Harvey J et al. 2003).

These can be divided into 3 subgroups (Takaya K et al.1996):

• Long isoforms: ObRb
• Short isoforms: ObRa, ObRc, ObRd and ObRf designated
• Soluble isoform: ObRe

Leptin itself is a target gene of the nuclear receptor PPARγ and thus also a target gene of RXRα, the heterodimeric partner of PPARγ. RXRα and PPARγ are probably also involved in the regulation of leptin in the placenta. RXR agonists are able to regulate leptin expression and thus positively influence the course of pregnancy.

The leptin receptor probably plays an important role in maintaining pregnancy. The ObR isoform, which is more abundant in the hypothalamus, regulates fat metabolism (Harvey J et al. 2003). In the absence of this receptor, mice develop obesity. Furthermore, a mutation in the ObR can cause gestational diabetes in pregnant mice (Yamashita H et al. 2001).

The signal transduction of the leptin receptor begins initially with the ligand binding of leptin to the receptor. This leads to the dimerization of two leptin receptors. The aggregation of two leptin receptors is promoted by the structural transformation of the receptor induced by ligand binding. Since the cytokine receptors do not have their own enzyme activity, they require the janus kinases (JAK) to activate the intracellular signalling cascade (Rassow J 2006). After JAK docks to ObR, JAK phosphorylates tyrosine residues of ObR, thereby creating binding sites for STAT (Signal Transducer and Activator of Transcription) proteins (Rassow J 2006). After binding of the STAT proteins, JAK phosphorylates them at a tyrosine residue. The STAT dimersof the aggregated ObR migrate into the cell nucleus and subsequently induce the transcription of the target genes (Schwartz MW et al. 2000).

1. Bado A et al (1998) The stomach is a source of leptin. Nature 394: 790-793.
2. Cervero A et al (2004) The leptin system during human endometrial receptivity and preimplantation development. J Clin Endocrinol Metab 89:2442-2451.
3. Conus S et al (2005) Leptin is an eosinophilic survival factor. J Allergy Clin Immunol 116:1228-1234.
4. Fantuzzi G et al (2000) Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68: 437-46.
5. Harvey J et al (2003) Leptin in the CNS: much more than a satiety signal. Neuropharmacology 44: 845-854.
6. Matarese G (2000) Leptin and the immune system: how nutritional status influences the immune response. Eur Cytokines Netw 11: 7-14.
7. Schwartz MW et al (2000) Central nervous system control of food intake. Nature 404: 661-671.
8. Takaya K et al.(1996) Molecular cloning of rat leptin receptor isoform complementary DNAs--identification of a missense mutation in sugar fatty (fa/fa) rat. Biochem Biophys Res Commun 225: 75-83.
9. Tartaglia LA et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83: 1263-1271.
10. Yamashita H et al (2001) Leptin administration prevents spontaneous gestational diabetes in heterozygous Lepr(db/+) mice: effects on placental leptin and fetal growth. Endocrinology 142: 2888-2897.